TRASCRIPTION FACTORS COOPERATE TO PROMOTE DOPAMINERGIC DIFFERENTIATION

Mesencephalic dopaminergic (mesDA) neurons are mainly located in ventral midbrain (substantia nigra and ventral tegmental area) and control voluntary movement, reward, attention and other cognitive processes. Their degeneration is related to Parkinson?s disease (PD), Attention Deficit Hyperactivity Disorder (ADHD) and other pathological conditions. During dopaminergic differentiation and maturation a great numbers of molecules (morphogens and trascription factors) are tightly regulated. Among these the transcription factor Nurr1 has a pivotal role in embryonic differention and maintenance in the adulthood of mesDA neurons. It regulates the expression of tyrosine hydroxylase (TH) and is essential for survival of the dopaminergic neurons. Lmx1a, another trascription factor, is expressed mainly in the early phases of dopaminergic differentiation even if recent works suggest its roles in late phases of development by regulating the expression of vescicular monoamine transporter 2 (VMAT2) and the dopamine transporter (DAT) both markers of mature mesDA neurons. In this work we reveal that Nurr1 and Lmx1a, act in a cooperative way to promote DA differentiation both in mouse mesencephalic primary cultures and in mesencephalic immortalized cell line (mes-c-myc-A1). Co-expression of Nurr1 with Lmx1a boosts the DA phenotype by increasing the levels of TH, VMAT2 and DAT. Interestingly by performing Luciferase reporter assays with Lmx1a and truncated constructs of Nurr-1 we observed that the C-terminal part of Nurr-1 is essential for this synergic activity. Taken togheter our results can help to clarify the mechanism of action of Nurr1 and provide new research avenues aimed to dissect the essential players in DA differentiation.